Chen Dan, Chen Xiao, He Cai, Xiao Chuntao, Chen Zelin, Chen Qizhu, Chen Jun, Bo Huaben
School of Bioscience and Biopharmaceutics, Guangdong Province, Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, 510006, Guangzhou, Guangdong, China.
College of Pharmacy, Guangdong Pharmaceutical University, 510006, Guangzhou, Guangdong, China.
J Ethnopharmacol. 2023 Apr 24;306:116162. doi: 10.1016/j.jep.2023.116162. Epub 2023 Jan 13.
Sanhuang Xiexin Decoction (SHXXD) is a classic prescription for the treatment of diabetes. Excessive hepatic glucose production (HGP) is a major determinant of the occurrence and development of diabetes. Inhibition of HGP can significantly improve type 2 diabetes mellitus (T2DM).
To investigate the mechanism by which SHXXD inhibits HGP.
First, a mouse model of T2DM was established through high-fat diet (HFD) feeding combined with streptozotocin (STZ) injection to determine the pharmacodynamic effect of SHXXD in T2DM mice. Then, the possible pathways induced by SHXXD in the treatment of T2DM were predicted by network pharmacology combined with transcriptomics (including target prediction, network analysis and enrichment analysis). Finally, the specific mechanism of SHXXD was elucidated by in vitro experiments.
In vivo experiments showed that SHXXD reduced fasting blood glucose and alleviated weight loss in T2DM mice. Improved glucose clearance rates and insulin sensitivity improve dyslipidemia, liver tissue structural abnormalities and inflammatory cell infiltration as well as increase glycogen storage in T2DM mice. The results of network pharmacology and transcriptome analysis showed that SHXXD contained 378 compounds and 2625 targets. In total, 292 intersection targets were identified between the differentially expressed genes (DEGs) of the liver tissue insulin resistance (IR) related dataset GSE23343. KEGG enrichment analysis showed that the insulin/PI3K-Akt/FoxO signaling pathway may be related to SHXXD-mediated improvements in T2DM. In vitro experimental results showed that SHXXD increased glucose consumption by HepG2-IR cells and improved their insulin sensitivity. RT‒qPCR and Western blotting results showed that SHXXD inhibited hepatic gluconeogenesis through the insulin/PI3K-Akt/FoxO signaling pathway by promoting IGFIR, PIK3R1 and AKT2 expression and subsequently inhibiting PEPCK and FBP1 expression via phosphorylation of Foxo1. In addition, PI3K/Akt deactivated p-GSK3β through phosphorylation, thereby promoting GS expression and increasing glycogen synthesis.
SHXXD can target the liver to cooperate with the insulin/PI3K-Akt/FoxO signaling pathway to inhibit HGP to alleviate T2DM.
三黄泻心汤（SHXXD）是治疗糖尿病的经典方剂。肝脏葡萄糖生成过多（HGP）是糖尿病发生发展的主要决定因素。抑制HGP可显著改善2型糖尿病（T2DM）。
探讨SHXXD抑制HGP的机制。
首先，通过高脂饮食（HFD）喂养联合链脲佐菌素（STZ）注射建立T2DM小鼠模型，以确定SHXXD对T2DM小鼠的药效学作用。然后，采用网络药理学结合转录组学（包括靶点预测、网络分析和富集分析）预测SHXXD治疗T2DM可能的作用途径。最后，通过体外实验阐明SHXXD的具体作用机制。
体内实验表明，SHXXD可降低T2DM小鼠的空腹血糖并减轻体重减轻。提高葡萄糖清除率和胰岛素敏感性，改善血脂异常、肝组织结构异常和炎性细胞浸润，并增加T2DM小鼠的糖原储存。网络药理学和转录组分析结果显示，SHXXD含有378种化合物和2625个靶点。在肝脏组织胰岛素抵抗（IR）相关数据集GSE23343的差异表达基因（DEG）之间共鉴定出292个交集靶点。KEGG富集分析表明，胰岛素/PI3K-Akt/FoxO信号通路可能与SHXXD介导的T2DM改善有关。体外实验结果表明，SHXXD可增加HepG2-IR细胞的葡萄糖消耗并改善其胰岛素敏感性。RT-qPCR和蛋白质印迹结果表明，SHXXD通过促进IGFIR、PIK3R1和AKT2表达，随后通过Foxo1磷酸化抑制PEPCK和FBP1表达，通过胰岛素/PI3K-Akt/FoxO信号通路抑制肝脏糖异生。此外，PI3K/Akt通过磷酸化使p-GSK3β失活，从而促进GS表达并增加糖原合成。
SHXXD可作用于肝脏，与胰岛素/PI3K-Akt/FoxO信号通路协同抑制HGP以减轻T2DM。
